Piperidine synthesis Reaction

FeX3 was also found to be an excellent promoter in the classical Prins cycliza-tion (Scheme 10, route H), with the observation of a satisfactory reaction between 3-buten-l-ol and several aldehydes, affording the corresponding c/s-4-halo-2-alkyl tetrahydrop3Tans in good yields [Eq. (1) in Scheme 32] [35], In a similar manner, the methodology can be extended to the piperidine synthesis through an aza-Prins cyclization [Eq. (2), Scheme 32] [41],... 

The excellent reducing properties of potassium tetracarbonylhydrido-ferrate have been used to good effect in providing an efficient general piperidine synthesis from alkyl and aryl amines and glutaraldehyde210 (Scheme 138). The reaction probably proceeds via reduction of intermediate Schiff bases and cyclization via the iminium salt. 

Piperidines. Grieco et al. have described a general synthesis of piperidines by reaction of the acid salt of a primary amine with an allylsilane and 2 equiv. of formaldehyde in water. The reaction involves reaction of iminium ion (a), derived from the amine and formaldehyde, with the allylsilane to form a homoallylamine (b), which can form a second iminium ion (c), which cyclizes with capture of water to the piperidine. 

The traditional route to piperidines by reaction between a 1,5-dihalopentane and ammonia or an amine is illustrated by the synthesis of 4-hydroxypiperidines (50) (88JCS(Pl)288l). 

Cross metathesis (CM) reactions can also be used as the key step in a piperidine synthesis (Scheme 40) <2004TL1167> or in sequence with ring-rearrangement metathesis, for example, in the synthesis of (—)-lasubine (Scheme 41) <2004T9629>. 

Grignard addition-cyclization reaction for piperidine synthesis... 

Harrity and co-workers have developed strategies for piperidine synthesis based on [3+3] cycloaddition reactions and have published a perspective on their and the work of other groups <05OBC1349>. The construction of 6-membered nitrogen heterocycles was included in a review of the [3+3] cycloaddition approach to natural product synthesis by Hsimg and coworkers <05EJO23>. 

A novel strategy for piperidine synthesis has been developed by Harrity and co-workers <01SL1596>. A variety of piperidines were synthesized in yields ranging from 63-82% by employing a [3+3] cycloaddition reaction between enantiomcrically pure aziridines 100 (generated from amino acids) and palladium trimcthylenemethane complexes (99). The efficiency of the methodology was demonstrated through a 4-step synthesis of (-)-pseudoconhydrine (101). 

The piperidine formation reaction has been applied for the total synthesis of allopumiliotoxine 267A [82]. 

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

Piperidine, 3-aryIoxymethyI-4-phenyI-as antidepressant, 1, 169 Piperidine, JV-bromo-photoelectron spectroscopy, 2, 142 Piperidine, cis-4- t-butyl-r- cyclohexyl-1 -phenyl-X-ray analysis, 2, 161 Piperidine, 3-chloro-pyrrolidines from, 4, 147 Piperidine, N-chloro-photoelectron spectroscopy, 2, 142 reactions, 2, 373 trimerization, 3, 510 Piperidine, 4-cycIopentyI-2,6-dioxo-synthesis... 

Pyrylium perchlorate, 2,4,6-triphenyl-hydrolysis, 3, 741 nitration, 3, 649 reactions with alkali, 3, 652 with methoxides, 3, 652 with piperidine, 3, 655 synthesis, 3, 869... 

HOFMANN - LOEFFLER FREYTAG Pyrrolidine Synthesis Synthesis of pyrrolidines or piperidines from N-haloamlnes (free radical reaction). 

The reactions of dichlorocarbene with morpholine and piperidine enamines derived from cyclopentanone and cyclohexanone have been reported to lead to ring expanded and a-chloromethylene ketone products (355,356). Similarly a-chloro-a, -unsaturated aldehydes were obtained from aldehyde derived enamines (357). Synthesis of aminocyclopropanes (353,359) could be realized by the addition of diphenyldiazomethane (360) and the methylene iodide-zinc reagent to enamines (367). 

Reaction of ethyl cyanoacetate with ethyl thiol acetate produces a and mixture of the dihydrothiazole derivative 80. This is ji-alkylated with methyl iodide and base (8 ), the active methylene group is brominated (82), and then a displacement with piperidine (83) is performed. Hydrolysis completes the synthesis of the diuretic agent, ozolinone (84). 

It has been found that the tris(tert-butyloxycarbonyl) protected hydantoin of 4-piperidone 2, selectively hydrolyses in alkali to yield the N-tert-butyloxycarbonylated piperidine amino acid 3. The hydrolysis, which is performed in a biphasic mixture of THF and 2.0M KOH at room temperature, cleanly partitions the deprotonated 4-amino-N -(tert-butyloxycarbonyl)piperidine-4-carboxylic acid into the aqueous phase of the reaction with minimal contamination of the hydrolysis product, di-tert-butyl iminodicarboxylate, which partitions into the THF layer. Upon neutralization of the aqueous phase with aqueous hydrochloric acid, the zwitterion of the amino acid is isolated. The Bolin procedure to introduce the 9-fluorenylmethyloxycarbonyl protecting group efficiently produces 4.8 This synthesis is a significant improvement over the previously described method9 where the final protection step was complicated by contamination of the hydrolysis side-product, di-tert-butyl iminodicarboxylate, which is very difficult to separate from 4, even by chromatographic means. 

A strategy involving sequential 1,3-dipolar cycloadditions has been reported for the synthesis of novel bis-isoxazolo substituted piperidines 192a and 192b (Eqs. 18 and 19) [53]. It consists of the Michael addition of an unsaturated alkox-ide 185 to )3-nitrostyrene 184 followed by an INOC or ISOC reaction to provide isoxazolines 187-189 (Eq. 18 and Table 18). A polymer supported acyl chloride... 

Morpholine also gives the allyhc amine in high yield. The reaction is thought to involve a known hydridopaUadium-catalyzed isomerization of alkynes to aUenes followed by reaction of the latter with the hydridopalladium complex to give 1-phenyl-substituted q -allylpalladium complexes. These complexes react with amines affording the allylic amines. Primary amines give the diallylic amines. An intramolecular version has been developed for the synthesis of 2-(2-phenyl)-pyrroUdines and -piperidines [319]. 

Reduction of the exocylic double bond and inclusion of the side chain nitrogen in a piperidine ring leads to a compound (19) which exhibits skeletal muscle relaxant activity. Its one step synthesis begins with reaction of thioxanthene (17) with phenyl sodium... 

---